Methods of preparing imidazole-based compounds

ABSTRACT

Methods of preparing imidazole-based compounds are disclosed. Particular compounds are of formula I.

This application is a continuation of U.S. patent application Ser. No.12/101,410, filed Apr. 11, 2008, which claims priority to U.S.provisional application No. 60/923,029, filed Apr. 12, 2007, theentireties of which are incorporated herein by reference.

1. FIELD OF THE INVENTION

This invention relates to methods of synthesizing imidazole-basedcompounds.

2. BACKGROUND

The compound1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone(THI) is a minor constituent of Carmel Color III, and reportedly lowerscirculating lymphocyte counts in rats. Methods of preparing THI havebeen reported. See, e.g., Kröplien, U. and Rosdorfer, J., J. Org. Chem.50:1131-1133 (1985); U.S. Pat. No. 4,567,194 to Kröplien et al.; Cliff,M. D. and Pyne, S. G., Tet. Lett. 36(33):5969-5972 (1995); Cliff, M. D.and Pyne, S. G., J. Org. Chem. 62:1023-1032 (1997). A particular methodreportedly provides THI in an overall yield of 46%. See Halweg, K. M.and Büchi, G., J. Org. Chem. 50:1134-1136, 1135 (1985).

It was recently reported that certain imidazole-based compounds arepotent inhibitors of immune response, and may be useful in the treatmentof diseases such as rheumatoid arthritis and type I diabetes. See U.S.patent application Ser. No. 11/698,253 to Augeri et al., filed Jan. 25,2007. In order to facilitate their testing and use, additional methodsof their synthesis are desired.

3. SUMMARY OF THE INVENTION

This invention encompasses methods of preparing compounds of formula I:

wherein: X is optionally substituted alkyl; R₁ is optionally substitutedalkyl; R₂ is hydrogen, halogen, nitrile, or optionally substitutedalkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle,alkylheterocycle, or heterocyclealkyl; and R₃ is hydrogen or optionallysubstituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle,alkylheterocycle, or heterocyclealkyl.

This invention also encompasses methods of increasing the major to minor(major:minor) isomer ratios of mixtures of compounds of formula I.

The invention also encompasses methods of preparing1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone.

4. BRIEF DESCRIPTION OF THE FIGURE

Aspects of this invention can be understood with reference to FIG. 1,which shows a ¹H NMR spectrum of a mixture of(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime.

5. DETAILED DESCRIPTION

This invention is based, in part, on the discovery of novel methods ofpreparing compounds of formula I. Particular methods are well suited forthe compounds' large-scale (e.g., kilogram scale) manufacture.

This invention is also based on the discovery of novel methods of making1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone.Particular methods afford the compound in high yield.

5.1. Definitions

Unless otherwise indicated, the term “alkenyl” means a straight chain,branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or2 to 6) carbon atoms, and including at least one carbon-carbon doublebond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and3-decenyl.

Unless otherwise indicated, the term “alkoxy” means an —O-alkyl group.Examples of alkoxy groups include, but are not limited to, —OCH₃,—OCH₂CH₃, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —O(CH₂)₄CH₃, and —O(CH₂)₅CH₃. Theterm “lower alkoxy” refers to —O-(lower alkyl).

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to4 carbons are referred to as “lower alkyl.” Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkylmoieties may be monocyclic or multicyclic, and examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.Additional examples of alkyl moieties have linear, branched and/orcyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term “alkyl”includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.

Unless otherwise indicated, the term “alkylaryl” or “alkyl-aryl” meansan alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or“alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or“alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain,branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2to 6) carbon atoms, and including at least one carbon-carbon triplebond. Representative alkynyl moieties include acetylenyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or anaromatic or partially aromatic ring system composed of carbon andhydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include anthracenyl, azulenyl,biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl,1,2,3,4-tetrahydro-naphthalene, and tolyl.

Unless otherwise indicated, the term “arylalkyl” or “aryl-alkyl” meansan aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “E:Z isomer ratio,” when referringto a mixture of an E isomer of a compound and its corresponding Zisomer, means the ratio of those isomers. Such ratios can be determinedby various methods known in the art, including chromatographic (e.g.,HPLC) and spectroscopic (e.g., NMR, Raman, and infrared absorption)methods.

Unless otherwise indicated, the terms “halogen” and “halo” encompassfluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term “heteroalkyl” refers to an alkylmoiety (e.g., linear, branched or cyclic) in which at least one of itscarbon atoms has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise indicated, the term “heteroaryl” means an aryl moietywherein at least one of its carbon atoms has been replaced with aheteroatom (e.g., N, O or S). Examples include acridinyl,benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl,indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, andtriazinyl.

Unless otherwise indicated, the term “heteroarylalkyl” or“heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “heterocycle” refers to anaromatic, partially aromatic or non-aromatic monocyclic or polycyclicring or ring system comprised of carbon, hydrogen and at least oneheteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e.,two or more) rings fused or bound together. Heterocycles includeheteroaryls. Examples include benzo[1,3]dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl,morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl and valerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or“heterocycle-alkyl” refers to a heterocycle moiety bound to an alkylmoiety.

Unless otherwise indicated, the term “heterocycloalkyl” refers to anon-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl” or“heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to analkyl moiety.

Unless otherwise indicated, the term “major:minor isomer ratio,” whenreferring to a mixture of a two isomers of a compound—the major isomer(i.e., the isomer present in greater than 50 weight percent) and itscorresponding minor isomer (i.e., the isomer present in less than 50weight percent)—means the ratio of those isomers. Such ratios can bedetermined by various methods known in the art, includingchromatographic (e.g., HPLC) and spectroscopic (e.g., NMR, Raman, andinfrared absorption) methods. When used to refer to a compoundcontaining an oxime moiety, the term “major:minor isomer ratio” refersto the oxime geometry. Thus, if a compound comprising an oxime moietyhas additional stereocenters, the term refers to the ratio ofdiastereomers comprising the oxime in one configuration to thediastereomers comprising the oxime in the other.

Unless otherwise indicated, the term “stereomerically enrichedcomposition of” a compound refers to a mixture of the named compound andits stereoisomer(s) that contains more of the named compound than itsstereoisomer(s). For example, a stereoisomerically enriched compositionof (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and(R)-butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10,95/5, and 98/2.

Unless otherwise indicated, the term “stereoisomeric mixture”encompasses racemic mixtures as well as stereomerically enrichedmixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and70/30).

Unless otherwise indicated, the term “stereomerically pure” means acomposition that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one stereocenterwill be substantially free of the opposite stereoisomer of the compound.A stereomerically pure composition of a compound having twostereocenters will be substantially free of other diastereomers of thecompound. A stereomerically pure composition of a compound that hasmultiple stereocenters, but which is drawn or named in such a way thatthe stereochemistries of less than all of its stereocenters are defined,is substantially free of the isomers of the compound that have differentstereochemistries at the stereocenters for which stereochemistry isdefined. For example, “stereomerically pure((1R)-1,2-dichloropropyl)benzene” refers to((1R)-1,2-dichloropropyl)benzene that is substantially free of((1S)-1,2-dichloropropyl)benzene.

A typical stereomerically pure compound comprises greater than about 80%by weight of one stereoisomer of the compound and less than about 20% byweight of other stereoisomers of the compound, greater than about 90% byweight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound, or greater thanabout 99% by weight of one stereoisomer of the compound and less thanabout 1% by weight of the other stereoisomers of the compound.

Unless otherwise indicated, the term “substituted,” when used todescribe a chemical structure or moiety, refers to a derivative of thatstructure or moiety wherein one or more of its hydrogen atoms issubstituted with an atom, chemical moiety or functional group such as,but not limited to, alcohol, aldehyde, alkoxy, alkanoyloxy,alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl),alkynyl, alkylcarbonyloxy (—OC(O)alkyl), amide (—C(O)NH-alkyl- or-alkylNHC(O)alkyl), amidinyl (—C(NH)NH-alkyl- or —C(NR)NH₂), amine(primary, secondary and tertiary such as alkylamino, arylamino,arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (—NHC(O)O-alkyl-or —OC(O)NH-alkyl), carbamyl (e.g., CONH₂, as well as CONH-alkyl,CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid,carboxylic acid anhydride, carboxylic acid chloride, cyano, ester,epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl(e.g., —CCl₃, —CF₃, —C(CF₃)₃), heteroalkyl, hemiacetal, imine (primaryand secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro,oxygen (i.e., to provide an oxo group), phosphodiester, sulfide,sulfonamido (e.g., SO₂NH₂), sulfone, sulfonyl (including alkylsulfonyl,arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl,thioether) and urea (—NHCONH-alkyl-).

Unless otherwise indicated, a “therapeutically effective amount” of acompound is an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or condition, or to delay orminimize one or more symptoms associated with the disease or condition.A therapeutically effective amount of a compound is an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of a disease or condition, or enhances thetherapeutic efficacy of another therapeutic agent.

Unless otherwise indicated, the terms “treat,” “treating” and“treatment” contemplate an action that occurs while a patient issuffering from the specified disease or disorder, which reduces theseverity of the disease or disorder, or one or more of its symptoms, orretards or slows the progression of the disease or disorder.

Unless otherwise indicated, the phrase “greater than X,” where X is anumber, has the same meaning as “X or greater than X.” Similarly, thephrase “greater than about X,” where X is a number, has the same meaningas “about X or greater than about X.”

Unless otherwise indicated, the phrase “less than X,” where X is anumber, has the same meaning as “X or less than X.” Similarly, thephrase “less than about X,” where X is a number, has the same meaning as“about X or less than about X.”

Unless otherwise indicated, the term “include” has the same meaning as“include” and the term “includes” has the same meaning as “includes, butis not limited to.” Similarly, the term “such as” has the same meaningas the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted alky, aryl, orheteroaryl” has the same meaning as “optionally substituted alky,optionally substituted aryl, or optionally substituted heteroaryl.”

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, the two phrases “XOH, wherein X is pyridyl” and “XOH,wherein X is pyridine” are accorded the same meaning, and encompass thecompounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or the portion of the structure is to beinterpreted as encompassing all stereoisomers of it. Similarly, names ofcompounds having one or more chiral centers that do not specify thestereochemistry of those centers encompass pure stereoisomers andmixtures thereof. Moreover, any atom shown in a drawing with unsatisfiedvalences is assumed to be attached to enough hydrogen atoms to satisfythe valences. In addition, chemical bonds depicted with one solid lineparallel to one dashed line encompass both single and double (e.g.,aromatic) bonds, if valences permit.

5.2. Methods of Synthesis

This invention encompasses a method of preparing a compound of formulaI:

wherein: X is optionally substituted alkyl; R₁ is optionally substitutedalkyl; R₂ is hydrogen, halogen, nitrile, or optionally substitutedalkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle,alkylheterocycle, or heterocyclealkyl; and R₃ is hydrogen or optionallysubstituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle,alkylheterocycle, or heterocyclealkyl; which comprises:

contacting a compound of formula II:

with a compound of formula III:H₂N—OR₃  IIIunder conditions sufficient for the formation of a mixture of E and Zisomers of a compound of formula I; and contacting the mixture of E andZ isomers with a strong acid.

Another embodiment encompasses a method of increasing the major:minorisomer ratio in a mixture of compounds of formula I:

which comprises:

contacting a solution comprising a first mixture of compounds of formulaI with a strong acid under conditions sufficient to provide a secondmixture of compounds of formula I, wherein:

the major:minor isomer ratio of the first mixture is less than themajor:minor isomer ratio of the second mixture; X is optionallysubstituted alkyl; R₁ is optionally substituted alkyl; R₂ is hydrogen,halogen, nitrile, or optionally substituted alkyl, aryl, alkylaryl,arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, orheterocyclealkyl; and R₃ is hydrogen or optionally substituted alkyl,aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle,or heterocyclealkyl.

In the various methods and embodiments disclosed herein, compounds(e.g., compounds of formulae I, II and/or III) may exist or be obtainedas solvates and/or salts.

In a particular embodiment, the solution comprises an alcohol (e.g.,methanol, ethanol, propanol or isopropanol).

In another, the solution is heated to a temperature of greater thanabout 30° C. (e.g., greater than about 40, 50 or 60° C.).

In another, the major:minor isomer ratio increases from less than about5:1 to greater than about 8:1. In another, the major:minor isomer ratioincreases from less than about 4:1 to greater than about 10:1. Inanother, the major:minor isomer ratio increases from about 3:1 togreater than about 13:1.

In another, the pH of the solution comprising the second mixture isincreased. In particular methods, the pH is increased to greater thanabout 6.0 (e.g., greater than about 7.0 or 8.0).

With reference to the various methods disclosed herein, as appropriate,particular embodiments are such that X is alkyl optionally substitutedwith one or more hydroxyl, acetate or halogen moieties.

In others, R₂ is hydrogen.

In others, R₃ is hydrogen.

In others, the compound of formula I is of formula I(a):

wherein: R₄ is OR_(4A), OC(O)R_(4A), N(R_(4B))₂, NHC(O)R_(4B), hydrogen,or halogen; R₅ is ° R_(5A), OC(O)R_(5A), N(R_(5B))₂, NHC(O)R_(5B),hydrogen, or halogen; R₆ is OR_(6A), OC(O)R_(6A), N(R_(6B))₂,NHC(O)R_(6B), hydrogen, or halogen; R₇ is alkyl, CH₂OR_(7A),CH₂OC(O)R_(7A), CH₂N(R_(7B))₂, CH₂NHC(O)R_(7B), hydrogen, or halogen;and each of R_(4A), R_(5A), R_(6A), R_(7A), R_(4B), R_(5B), R_(6B), andR_(7B) is independently hydrogen or optionally substituted alkyl, aryl,alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, orheterocyclealkyl.

In others, the compound of formula I(a) is a stereomerically purecompound of formula I(b):

Referring to structures I(a) and (b), particular embodiments of theinvention are such that one or more of R₄, R₅, and R₆ is hydroxy orhalogen. In others, all of R₄, R₅, and R₆ are hydroxyl or acetate.

Examples of strong acids include hydroiodic, hydrobromic, hydrochloric,sulfuric, nitric, phosphoric, alkanesulfonic, and arenesulfonic acid.

A specific embodiment of the invention is represented below, in Scheme1:

In this method, the E:Z isomer ratio in a mixture of(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime is increased.

The method comprises contacting a solution comprising a first mixture of(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime with a strong acid under conditions sufficient to provide a secondmixture of(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime; wherein the E:Z isomer ratio of the first mixture is less thanthe E:Z isomer ratio of the second mixture.

In a particular embodiment, the first mixture is prepared by contacting1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanonewith hydroxylamine under conditions sufficient for the formation of1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime. The1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanonecan be prepared by contacting 1-amino-1-deoxy-D-fructose with2-ethoxyacrylonitrile under conditions sufficient for the formation of1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone,as shown below in Scheme 2:

Advantageously, this invention provides novel methods of making1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone.

One embodiment encompasses a method of preparing1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone,which comprises: adding a first portion of sodium methoxide to asolution comprising 2-ethoxyacrylonitrile to provide a first mixture;contacting the first mixture with 1-amino-1-deoxy-D-fructose to providea second mixture; adding a second portion of sodium methoxide to thesecond mixture to provide a third mixture; adding acetic acid to thethird mixture to provide a fourth mixture; and mixing the fourth mixturefor a time and at a temperature sufficient for the formation of1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone.

In a particular method, the second mixture is maintained at atemperature of greater than about 5° C. (e.g., greater than about 10, 15or 20° C.).

In another, the first mixture is maintained at a temperature of greaterthan about 5° C. (e.g., greater than about 10, 15 or 20° C.).

In another, the first portion of sodium methoxide is added as a solutionof greater than about 15 weight percent (e.g., greater than about 20 or25 weight percent) sodium methoxide in methanol.

In another, the second portion of sodium methoxide is added as asolution of greater than about 15 weight percent (e.g., greater thanabout 20 or 25 weight percent) sodium methoxide in methanol.

In another, the 1-amino-1-deoxy-D-fructose is provided in a slurryfurther comprising its acetic acid salt.

In another, the third mixture is diluted with water before the aceticacid is added to it.

In another, the fourth mixture is heated to a temperature of greaterthan about 30° C. (e.g., greater than about 35, 40, 45, 50, 55, or 60°C.).

In another, the fourth mixture is heated for less than about 5 hours(e.g., less than about 4, 3, or 2 hours).

In another, the1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone isisolated with a yield of greater than about 50 percent (e.g., greaterthan about 55, 60, 65, 70, 75, or 80 percent).

6. EXAMPLES

Aspects of this invention can be understood from the following examples,which do not limit its scope.

6.1. Example 1 Preparation of Ethoxyacrylonitrile

To a 250 ml jacketed 3-neck round bottom flask with magnetic stir bar,rubber septum with temperature probe, plastic stopper, andpressure-equalized addition funnel with gas bubbler was charged withbromoacetaldehyde diethylacetal (35.33 g/179.28 mmol) and tin (II)chloride (167.1 mg/0.88 mmol/0.5 mol %). The suspension was cooled to 3°C. Then trimethylsilyl cyanide (17.69 g/178.31 mmol) was added over 11minutes at a temperature below 15° C. The mixture was held at about 10°C. for 35 minutes and then at about 20° C. for at least 1.75 hours oruntil GC analysis showed consumption of bromoacetaldehyde diethylacetal.

The above light yellow solution was diluted with 85 ml MTBE.Diethylamine (19.61 g, 268.11 mmol/1.50 equiv.) was added over 6 minutesat a temperature below 35° C. The resulting thick slurry was dilutedwith additional 25 ml MTBE. The reaction mixture was stirred at about25° C. for at least 1.75 hours or until reaction completion by GCanalysis. The mixture was filtered and the collected solids were washedMTBE (2×30 ml). The combined filtrate was concentrated under vacuum(final vacuum: about 95 torr). The resulting crude ethoxyacrylonitrile(17.46 g) was polish-filtered and vacuum distilled to give a clearliquid (11.2 g, 67% yield). B.p.: 46-49° C./31 mm Hg. ¹H NMR (CDCl₃) δ4.85 (d, J=3.54 Hz, 1H), 4.75 (d, J=3.28 Hz, 1H), 3.73 (q, J=6.99 Hz,2H), 1.24 (t, J=6.95 Hz, 3H). ¹³C NMR (CDCl₃) δ 136.58, 115.23, 101.11,65.54, 14.40.

6.2. Example 2 Preparation of1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone

To a 3-neck, 12-L round bottom flask equipped with a mechanical stirrer,a temperature controller was added ethoxyacrylonitrile (100.0 g, 1.03mol) and methanol (HPLC grade, 1.0 L, 10×). To the above stirredsolution was added sodium methoxide in methanol (25 wt %, 140.6 ml, 0.60equiv) in over 15 minutes. The mixture was stirred at 20° C. for atleast 3 hours or until ¹H NMR showed at least 95% conversion of theethoxyacrylonitrile to the corresponding imidate). The above solutionwas transferred to a slurry of fructosamine acetic acid salt (246.9 g,1.0 equiv, prepared according to Hodge, J. E.; Fisher, B. E., Methods inCarbohydrate Chemistry 11:99-103 (1963)) in methanol (1.0 L, 10×) over15 min and the mixture was stirred at 20° C. for 6 hours. Anotherportion of sodium methoxide in methanol (25 wt %, 117.3 ml, 0.50 equiv)was added to the mixture over 10 minutes and the mixture stirred at 20°C. for additional 16 hours.

The mixture was then diluted with water (2.0 L, 20×) and treated withacetic acid (118 ml, 2.0 equiv). After stirring at 60° C. for 1 h, thesolution was concentrated (50° C., 200 mbar-70 mbar) to 1.2 L totalvolume. The slurry mixture was cooled to 0° C. and stirred for 1 h, thenfiltered and the solids were washed with water (100 ml, ×2). The solidswere collected and dried under vacuum at 50° C. to afford 196.8 g crudeproduct as a pale yellow solid, which was then treated with water (980ml, 5×) and the resulting slurry was heated to boiling for 15 min, thenre-cooled to 0° C. and stirred for an additional 1 h. The mixture wasagain filtered, and the solids were washed with water (100 ml, ×2) anddried to constant weight in a vacuum oven at 50° C. to provide 194.8 g(82%) of the title product (THI) as a pale yellow solid (KF=0.4%). ¹HNMR (D₂O w/a drop of DCl in D₂O) 7.48 (d, J=2.0 Hz, 0.9H), 7.19 (d,J=2.0 Hz, 0.1H), 5.09 (s, 0.9H), 4.98 (s, 0.1H), 3.40-3.70 (m, 4H), 2.53(d, J=2.4 Hz, 3H); ¹³C NMR (D₂O w/a drop of DCl in D₂O) 185.0, 139.4,138.0, 119.5, 73.0, 70.9, 65.0, 63.2, 26.7; MH⁺=231.2.

6.3. Example 3 Preparation of(E)-1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneOxime Dihydrate

To a 3-neck, 3-L round bottom flask equipped with a mechanical stirrer,a temperature controller and a condenser were charged with1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone(100.0 g, 434.4 mmol), hydroxylamine hydrochloric acid salt (45.2 g, 1.5equiv), sodium acetate (53.4 g, 1.5 equiv) and methanol (HPLC grade, 1.0L, 10×). The above solution was heated at 65° C. with stirring for 2 h.

To the mixture was then added a solution of HCl in isopropanol (freshlyprepared by slow addition of 92.7 ml acetyl chloride to 200 mlisopropanol at 0° C., 3.0 equiv) over 15 min and resulting mixturestirred at 65° C. for 3 h. The mixture was diluted with MeOH (1.0 L,10×) and cooled to room temperature and the precipitated sodium chloridewas removed by filtration. The solids were washed with MeOH (100 ml, 1×)and the solution was concentrated at 40° C. under vacuum until solidsstarted to form (about 200 ml). Water (1.0 L, 10×) was then added andthe residual organic solvents were removed at 40° C. under vacuum. Apolish filtration was performed to afford a clear yellow solution. Tothis solution was slowly added 50% NaOH aqueous solution at roomtemperature so that the temperature of the mixture did not exceed 40°C., until the pH reached 7.2 (7.0-7.5). The resulting solution was thenheated to 65° C. to form a homogeneous solution, and concentrated undervacuum at 65° C. (60-70° C.) until the solution reached about 500 ml(5×) overall volume. The mixture was then cooled to room temperatureslowly, further cooled to 0° C., and stirred at 0° C. for 1 h. Thesolids were collected by filtration and washed with water (0° C., 100ml, 1× ×2) to afford a white crystalline solid.

To the above wet solid was added water (400 ml) and the resultingmixture was heated to 70-80° C. until all dissolved. The solution wascooled to room temperature and then stirred at 0° C. for 1 h. The solidswere collected by filtration and washed with water (0° C., 100 ml, 1××2) and then dried under vacuum at 30° C. overnight to afford 99.4 g ofthe title compound. NMR analysis showed that the material containedabout 3% of the Z isomer.

6.4. Example 4 Preparation of Anhydrous(E)-1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneOxime

The solid from Example 3 was slurried with EtOH (800 ml, 8×) and heatedat 75° C. for 1 h. The resulting mixture was cooled to 0° C. and stirredat 0° C. for 1 h. The white solid was collected by filtration and washedwith EtOH (0° C., 100 ml, 1×, ×2) and dried at 50° C. under vacuum toconstant weight to give the title compound. NMR analysis showed about 2%of the Z isomer. ¹H NMR (D₂O) 7.05 (s, 1H), 4.83 (d, J=3.6 Hz, 1H),3.60-3.80 (m, 3H), 3.50 (dd, J=11.6, 6.8 Hz, 1H), 2.11 (d, J=4.0 Hz,3H); ¹H NMR (D₂O w/a drop of DCl in D₂O) 7.30 (s, 1H), 5.04 (s, 1H),3.45-3.75 (m, 4H), 2.13 (s, 3H); ¹³C NMR (D₂O w/a drop of DCl in D₂O)143.8, 140.9, 135.0, 116.9, 72.5, 70.6, 64.4, 62.7, 10.5; MH⁺=246.1.

6.5. Example 5 Determination of E:Z Isomers Ratios

The relative amounts of E and Z isomers of compounds of Formula I can bedetermined by a variety of techniques known in the art. For example, therelative amounts of(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime in a mixture of the two can be readily determined by NMR, as shownin FIG. 1.

All cited publications, patents, and patent applications are hereinincorporated by reference in their entireties.

1. A composition compising an alcohol and(E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime and(Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanoneoxime in an E:Z isomer ratio that is greater than 8:1.
 2. Thecomposition of claim 1, wherein the E:Z isomer ratio is greater than10:1.
 3. The composition of claim 2, wherein the E:Z isomer ratio isgreater than 13:1.
 4. The composition of claim 1, wherein the alcohol ismethanol, ethanol, propanol, or isopropanol.
 5. The composition of claim4, wherein the alcohol is methanol.
 6. The composition of claim 1, whichis acidic.
 7. The composition of claim 6, which is acidic due to theaddition of an acid which is hydroiodic, hydrobromic, hydrochloric,sulfuric, nitric, phosphoric, alkanesulfonic, or arenesulfonic acid. 8.The composition of claim 7, wherein the acid is hydrochloric acid.